Ral A, via activating the mitotic checkpoint, sensitizes cells lacking a functional Nf1 to apoptosis in the absence of protein kinase C
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Suthakar Ganapathy1,*, Johan B Fagman2,*, Ling Shen1, Tianqi Yu1, Xiaodong Zhou1,3, Wei Dai4, Alexandros Makriyannis1, Changyan Chen1
1Center for Drug Discovery, Northeastern University, Boston, MA, USA
2The Institute of Clinic Sciences, Sahlgrenska Academy, Gothenburg, SE
3The First Affiliated Hospital of Nanchang University, Nanchang, China
4Department of Environmental Medicine, New York University, Tuxedo, NY, USA
*These authors contributed equally to this work
Changyan Chen, email: email@example.com
Keywords: Nf1, Ral A, Chk1, mitotic catastrophe, apoptosis
Received: August 01, 2016 Accepted: October 04, 2016 Published: October 12, 2016
Nf1 mutations or deletions are suggested to underlie the tumor predisposition of NF1 (neurofibromatosis type 1) and few treatments are available for treating NF1 patients with advanced malignant tumors. Aberrant activation of Ras in Nf1-deficient conditions is responsible for the promotion of tumorigenesis in NF1. PKC is proven to be an important factor in supporting the viability of Nf1-defected cells, but the molecular mechanisms are not fully understood. In this study, we demonstrate that the inhibition of protein kinase C (PKC) by 1-O-Hexadecyl-2-O-methyl-rac-glycerol (HMG, a PKC inhibitor) preferentially sensitizes Nf1-defected cells to apoptosis, via triggering a persistent mitotic arrest. In this process, Ral A is activated. Subsequently, Chk1 is phosphorylated and translocated to the nucleus. Silencing Ral A significantly blocks Chk1 nuclear translocation and releases HMG-treated Nf1-deficient cells from mitotic arrest, resulting in the reduction of the magnitude of apoptosis. Thus, our study reveals that PKC is able to maintain the homeostasis or viability of Nf1-defected cells and may serve as a potential target for developing new therapeutic strategies.
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